Novel 99mTc(III) Complexes as SPECT Radiotracers for MPI

描述(申请人提供)：在这个项目中，我们将评估8个新的99mTc(III)配合物[99mTc(S-R)(CDO)(CDOH)2B-Me](R=P1-P24)作为SPECT心肌灌注显像剂。SD大鼠将被用来评估它们的心脏摄取和生物分布。这些研究旨在回答以下三个基本问题：(1)它们是否能够定位并在心脏内保留(高摄取率和长期心肌滞留)？(2)聚乙二醇组对99mTc放射性示踪剂的心脏摄取和肝脏清除有何影响？(3)就心脏摄取、心肌滞留和心/肝比率而言，哪种示踪剂是最好的？该项目的主要目标是增加新型99mTc(III)放射性示踪剂的心肌滞留和最大限度地减少肝脏摄取，同时保持其高心脏摄取。假设与策略：我们假设硫酸盐能够通过阻止99mTc(III)配合物[99mTC(S-R)(CDO)(CDOH)2BMe](R=P1-P24)在体内的水解来增加99mTc(III)的心肌保留率，因为硫代-S与Tc(III)形成了比氯更强的键。我们还假设聚醚基团可以增加99mTc(III)络合物的心肌滞留和肝脏清除，因为聚乙二醇基可以增加治疗药物的血液保留时间，而且我们的研究清楚地表明，聚醚基团能够改善阳离子99mTc放射性示踪剂的肝脏清除。为了检验这些假设，我们开发了一个分两步走的策略。在第一步中，我们将制备[99mTc(S-R)(CdO)(CDOH)2B-Me](R=P1-P24)。不同的R基团被用来平衡它们的亲脂性，以便它们的心脏摄取和T/B比率可以系统地优化。在第二步中，我们将评估它们在SD大鼠的心脏摄取和生物分布。为便于比较，将始终使用99mTc-Teboroxime作为对照。这些研究的结果将使我们能够为今后的进一步评价选择最佳候选人。临床意义。目前有超过7000万美国人患有心血管疾病，每年有91万人死于心血管疾病。对冠心病患者进行快速准确的诊断是非常必要的，这样才能给出合适的治疗方案。该项目的资助和成功完成可能导致新的99mTc放射性示踪剂具有非常高的一次通过提取分数，心脏/肝脏比率远远好于99mTc-特波罗昔姆。较高的心脏摄取率和较好的心脏/肝脏比率将使图像能够及早获得，并通过减少肝脏放射性的散射来改善图像质量。高的首过提取和血流速度与放射性示踪剂心肌摄取之间的线性关系将允许更好地检测冠状动脉疾病的存在和程度，以及更准确地描绘心肌灌注缺陷，这对于治疗已知或疑似冠心病的患者和评估未来心脏事件，特别是心肌梗死和死亡的风险有相当大的好处。

DESCRIPTION (provided by applicant): In this project, we will evaluate 8 novel 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R = P1 - P24) as SPECT radiotracers myocardial perfusion imaging. Sprague-Dawley (SD) rats will be used to evaluate their heart uptake and biodistribution. These studies are designed to answer the following three fundamental questions: (1) Are they able to localize and retain in heart (high heart uptake and long myocardial retention)? (2) What is the impact of PEG groups on heart uptake and liver clearance of 99mTc radiotracers? (3) Which is the best radiotracer with respect to the heart uptake, myocardial retention and heart/liver ratios? The main objective of this project is to increase the myocardial retention and minimize liver uptake of novel 99mTc(III) radiotracers while maintaining their high heart uptake. Hypothesis and Strategy: We hypothesize that thiolates are able to increase the myocardial retention of their 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2BMe] (R = P1 - P24) by preventing their hydrolysis in vivo because thiolate-S forms a stronger bond with Tc(III) than Cl. We also hypothesize that polyether groups will increase the myocardial retention and liver clearance of 99mTc(III) complexes since it has been well-established that PEG groups can increase the blood retention times of therapeutics, and our studies clearly showed that polyether groups are able to improve liver clearance of cationic 99mTc radiotracers. To test these hypotheses, we developed a two-step strategy. In first step, we will prepare complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R = P1 - P24). Different R groups are used to balance their lipophilicity so that their heart uptake and T/B ratios can be optimized in a systematic fashion. In the second step, we will evaluate their heart uptake and biodistribution in SD rats. 99mTc-Teboroxime will be always used as the control for comparison purposes. The results from these studies will allow us to select an optimal candidate for further evaluations in the future. Clinical Significance. More than 70 million Americans currently live with cardiovascular diseases, which lead to >910,000 deaths each year. Rapid and accurate diagnosis in CAD patients is highly desirable so that appropriate therapeutic regimens can be given. Funding and successful completion of this project may lead to new 99mTc radiotracers that have very high first-pass extraction fraction with the heart/liver ratios much better than tha of 99mTc-Teboroxime. High heart uptake with better heart/liver ratios will allow for early acquisition of images, and improve the image quality by reducing scatter from liver radioactivity. High first-pass extraction and linear relationship between the blood flow rate and the radiotracer myocardial uptake will permit better detection of the presence and extent of coronary disease, and more precise delineation of myocardial perfusion defects, which is of considerable benefit in management of patients with known or suspected CAD and assessing risk of future cardiac events, particularly myocardial infarction and death.